Summary Mild Cognitive Impairment (MCI) is a preclinical form of Alzheimer's Disease (AD), characterized by cognitive deficits that are intermediate between those observed in healthy aging and AD. Amnestic multi-domain MCI (aMCI-MD) is a subtype of MCI with high (~40%) rates of conversion to AD, representing a valuable cohort for mechanistic studies of AD pathophysiology at a relatively early phase. The primary pathological/imaging finding in AD/MCI is of abnormal protein deposition in brain tissue, but the mechanisms by which this deposition is initiated and ultimately results in cognitive decline, are poorly understood. Recent developments in edited magnetic resonance spectroscopy (MRS) have substantially accelerated measurements of low- concentration metabolites of key interest in MCI, including redox compounds (glutathione and ascorbate), neurotransmitters and neuromodulators (GABA, glutamate, aspartate and N-acetylaspartylglutamate), and other compounds including the anaerobic product lactate. In this study, we will apply the new editing experiment HERCULES (Hadamard Editing Resolves Chemicals Using Linear Estimation of Spectra) to measure levels of these metabolites in three pathologically important brain regions (medial temporal lobe, anterior and posterior cingulate) in subjects with aMCI-MD and age- and sex-matched healthy controls. We will also test hypothesized relationships between neurochemistry and cognitive outcomes, and between MRS metabolite levels and prior PET imaging of amyloid-? and tau protein deposition.